Lecture 11 - Neurotrophic Factors II Flashcards
What are the Statistics for Parkinson’s disease?
- 2nd most common neurodegenerative disorder after Alzheimer’s disease.
- Incurable & progressive disease.
- Afflict 0.3% of the general population worldwide.
- Occurs in all ethnic groups.
- Appears to be somewhat more common in men
- Associated with significant disability & substantial decrease in quality of life.
- Increase with age
What is the Diagnosis for Parkinson’s?
Mostly Idiopathic/sporadic & < 10% familial parkinsons.
Definition
Asymmetry with
- Resting tremor.
- Rigidity.
- Bradykinesis.
- Postural instability (non-specific & usually absent in early state of disease).
- Increasing evidence of non-motor dyfunctions before motor signs of Parkinson’s disease -
Patients also exhibit sleep disturbance, autonomic dysfunction, hyposmia, cognitive decline and depression.
Other characteristics of PD
- Presence of “Lewy bodies” in the neurons of SN — postmortem
- 75% of PD patients have LB — not all.
- What is in these neuron — apoptosomes/ and other proteins
- α-synuclein: Not definitive for PD, Incidental α-synuclein pathology in the normal aging brain, with frequencies of 8%—22.5% in normal aging and 34.8% in centenarians
Appears that “more than one road lead to Rome”.
i.e., PD is a syndrome of multiple causes
AnnRevMed 55:41-60
Other “Parkinsonism” with similar symptoms
What are ther clinical syndromes showing some similarities?
- Subcortical degenerations (e.g., Huntington’s disease, progressive supranuclear
palsy). - Cortical degenerations (e.g., Alzheimer’s disease, CJD, hydrocephalus).
- Encephalitis (e.g., Encephalitis lethargica, viral infections).
- Toxins (e.g., MPTP, CO, pesticides)
- Drugs (e.g., Dopamine receptor blockers).
Proposed model of development of premotor symptoms
u Comparison among persons who will or will not develop PD in lifetime
What does it show?
Significant number of DA neuron would have died at point of diagnosis
What regions are affected in Parkinson’s disease?
Basal ganglia - dopaminergic neurons
Other neurotransmitter pathways
Other areas
What makes substantia Nigra DA neuron vulnerable?
Disproportionately large toxic burden (a-synuclein ) on the machinery for cellular transport and synaptic release.
Each human SNC DA neuron
1-2.5 million synapses in the striatum
Total axonal length in > 4 m
What is a chemotherapeutic for Parkinson’s disease?
L-Dopa (precursor to dopamine)
But 10-14% of patients on dopamine agonists: impulse-control disorders, turning some into gamblers.
What are the traits of L-Dopa Therapy?
- Managing disease
- ‘Honey-Moon’ years
- Efficacy decline with progression of disease
- Dosage titration is difficult in late stages. Side effects
What protects neuron from dying in S. NIGRA?
GENETICS V. ENVIRONMENTS
Protective effects noted for:
- cigarette smoking, a/coho/and caffeine intake.
Unclear how they influence disease risk
Not magic but science
- Caffeine — largely act as brain adenosine A2A receptor (A2AR) antagonist
- Istradefylline (FDA approved 2019) as a ‘levodopa sparing’ strategy
How does MPTP cause signs of Parkinsonism?
Goes inside glial cells, becomes oxidised, goes inside dopaminergic neurons and blocks enzymes in respiratory system
What are other forms of Chemical induced Parkinsonism?
Paraquat - herbicide
Rotenone
- Rotenone — Mitochondrial inhibitor
- 6-OH-DA — inject into striatum & retrogradely destroy SN neuron
- Proteosome inhibitors (inhibit “protein handling”) e.g. Epoxomycin
How do genes influence PD?
Some Genes involved in familial PD
- Majority of PD -idiopathic (90—95%) with no specific known cause
- 5-10% remaining ones are familial forms
What are some Proposed mechanisms/ interactions in the dopaminergic cells of the substantia niqra in PD?
Principle defects
- Misfolding/inclusion body.
- Metabolism
- Protein turn-over
- Impaired intracellular trafficking
International conference on harmonization (ICH) - 1990
US/ EUROPE/ JAPAN
What was it about?
Development of a COMMON TECHNICAL DOCUMENT (CTD) - standardizing global drug application procedures.
Reduce duplication of preclinical/clinical requirements for new drugs/medicine — expedite drug acceptance in different countries.
Safeguards on:
- Quality
- Safety
- Efficacy
- Regulatory obligations to protect pubic health.
